Meta-regression of idiopathic full-thickness macular holes diameter and anatomical closure rate: Implications to intraoperative technique.

Purpose: Primary surgery failure of macular holes causes poor visual acuity outcomes. Several studies indicate that small-medium idiopathic full-thickness macular holes (iFTMH) have consistent and high anatomical closure rates after vitrectomy and internal limiting membrane (ILM) peeling, regardless of iFTMH diameters. However, there is no systematic analysis examining the relationship between iFTMH diameters and anatomical closure rates. Methods: In this systematic review and meta-regression, we searched PubMed, Embase, and Web of Science databases on October 24th, 2022. We included studies regarding iFTMH, with ILM peeling/inverted flap technique, long-lasting gas tamponade, and face-down position after surgery. Univariable meta-regression with a restricted cubic spline model and component-plus-residual plot after covariables adjustment were used to explore non-linear association. Results: A total of 7257 participants from 19 randomized controlled trials and 49 observational studies were included in this meta-analysis. In ILM peeling group, every 100-µm increment in diameter was associated with a 3.8 % (95 % confidence interval [CI], 1.8%-5.7 %, P < 0.001) relatively lower anatomical closure rate. Yet, among studies using the inverted flap technique, baseline iFTMH diameter was not associated with a lower anatomical closure rate (0.2 %, 95%CI, -4.2 %-4.5 %, P > 0.9). The restricted cubic spline model and component-plus-residual plot controlling for age, sex, and symptom duration prior to surgery showed no evident non-linearity in both surgical techniques. Conclusions: The iFTMH diameter is linear and inversely associated with the anatomical closure rate after the ILM peeling technique, but not with the inverted flap technique. The present study supports the use of advanced techniques, e.g., inverted flap technique, in small-medium iFTMH to improve anatomical closure rates.

[Mechanism of HOXC6 promoting the progression of prostate cancer by activating the SFRP1/Wnt/ß-catenin signaling pathway].

OBJECTIVE: To study the expression of the Homeobox C6 (HOXC6) gene in the homeobox family in PCa, its effect on the biological behavior of PCa cells and its action mechanism. METHODS: Based on the studies of HOXC6 retrieved from the database of Gene Expression Profiling Interactive Analysis (GEPIA), we analyzed the expression of HOXC6 in PCa and the relationship of its expression level with the survival prognosis of the patients. We detected the expression of the HOXC6 protein in PCa tissues and cells by Western blot, stably interfered with the expression of the HOXC6 gene in human PCa DU145 and PC-3 cells and normal prostatic epithelial RWPE-1 cells using the siRNA plasmid, and determined the effects of HOXC6 on the proliferation, migration and invasiveness of PCa cells by CCK8, plate cloning and scratch healing and Transwell invasion assays. Using the GEPIA database, we analyzed the correlation of the Wnt tumor inhibitory factor-secreted frizzled-related protein 1 (SFRP1) gene with HOXC6, and detected the expressions of HOXC6, SFRP1, Wnt and ß-catenin in PC-3 cells after siRNA-HOXC6 transfection by Western blot. RESULTS: The expression of HOXC6 was dramatically higher in the PCa than in the normal prostate tissue (P< 0.01), and in the PCa cells than in the normal prostatic epithelial cells (P< 0.01). Bioinformatics analysis indicated a lower survival rate of the PCa patients with a high than those with a low HOXC6 expression (P = 0.011). The relative expression of the HOXC6 protein, absorbance value, number of clones formed and number of invaded cells were significantly lower in the siRNA group than in the negative controls (P< 0.05). According to the GEPIA database, highly expressed SFRP1 was associated with a good prognosis of PCa, and the protein expressions of Wnt and ß-catenin were markedly increased while that of SFRP1 decreased in the PCa PC-3 cell line (P< 0.05). The expressions of the Wnt and ß-catenin proteins were decreased and that of SFRP1 increased significantly in the siRNA-HOXC6 transfection group compared with those in the siRNA negative control and PCa PC-3 groups (P< 0.05). CONCLUSION: HOXC6 is highly expressed in PCa tissues and related to the proliferation, migration and invasiveness of PCa cells. HOXC6 promotes the growth of DU145 and PC-3 cells in PCa by inhibiting the SFRP1/Wnt/ß-catenin signaling pathway, and may be a potential target for clinical treatment of PCa.

Circulating metabolic biomarkers and risk of new-onset hypertension: findings from the UK Biobank.

OBJECTIVE: The evidence regarding the associations of circulating metabolic biomarkers with hypertension risk is scarce. We aimed to examine the associations between circulating metabolites and risk of hypertension. METHODS: We included 49 422 individuals free of hypertension at baseline with a mean (SD) age of 53.5 (8.0) years from the UK Biobank. Nuclear magnetic resonance spectroscopy was used to quantify 143 individual metabolites. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% confidence intervals (CIs). RESULTS: During a mean (SD) follow-up of 11.2 (1.8) years, 2686 incident hypertension cases occurred. Out of 143 metabolites, 76 were associated with incident hypertension, among which phenylalanine (hazard ratio: 1.40; 95% CI: 1.24-1.58) and apolipoprotein A1 (hazard ratio: 0.76; 95% CI: 0.66-0.87) had the strongest association when comparing the highest to the lowest quintile. In general, very-low-density lipoprotein (VLDL) particles were positively, whereas high-density lipoprotein (HDL) particles were inversely associated with risk of hypertension. Similar patterns of cholesterol, phospholipids, and total lipids within VLDL and HDL particles were observed. Triglycerides within all lipoproteins were positively associated with hypertension risk. Other metabolites showed significant associations with risk of hypertension included amino acids, fatty acids, ketone bodies, fluid balance and inflammation markers. Adding 10 selected metabolic biomarkers to the traditional hypertension risk model modestly improved discrimination (C-statistic from 0.745 to 0.752, P < 0.001) for prediction of 10-year hypertension incidence. CONCLUSION: Among UK adults, disturbances in metabolic biomarkers are associated with incident hypertension. Comprehensive metabolomic profiling may provide potential novel biomarkers to identify high-risk individuals.

Associations of Heavy Metals with Cognitive Function: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.

OBJECTIVE: Exposure to heavy metals has been reported to be associated with impaired cognitive function, but the underlying mechanisms remain unclear. This pilot study aimed to identify key heavy metal elements associated with cognitive function and further explore the potential mediating role of metal-related DNA methylation. METHODS: Blood levels of arsenic, cadmium, lead, copper, manganese, and zinc and genome-wide DNA methylations were separately detected in peripheral blood in 155 older adults. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Least absolute shrinkage and selection operator penalized regression and Bayesian kernel machine regression were used to identify metals associated with cognitive function. An epigenome-wide association study examined the DNA methylation profile of the identified metal, and mediation analysis investigated its mediating role. RESULTS: The MMSE scores showed a significant decrease of 1.61 (95% confidence interval [CI]: -2.64, -0.59) with each 1 standard deviation increase in ln-transformed arsenic level; this association was significant in multiple-metal models and dominated the overall negative effect of 6 heavy metal mixture on cognitive function. Seventy-three differentially methylated positions were associated with blood arsenic (p < 1.0 × 10-5). The methylation levels at cg05226051 (annotated to TDRD3) and cg18886932 (annotated to GAL3ST3) mediated 24.8% and 25.5% of the association between blood arsenic and cognitive function, respectively (all p < 0.05). INTERPRETATION: Blood arsenic levels displayed a negative association with the cognitive function of older adults. This finding shows that arsenic-related DNA methylation alterations are critical partial mediators that may serve as potential biomarkers for further mechanism-related studies. ANN NEUROL 2024;96:87-98.

Cost-Effectiveness of a Workplace-Based Hypertension Management Program in Real-World Practice in the Kailuan Study.

BACKGROUND: In 2009, a workplace-based hypertension management program was launched among men with hypertension in the Kailuan study. This program involved monitoring blood pressure semimonthly, providing free antihypertensive medications, and offering personalized health consultations. However, the cost-effectiveness of this program remains unclear. METHODS AND RESULTS: This analysis included 12 240 participants, with 6120 in each of the management and control groups. Using a microsimulation model derived from 10-year follow-up data, we estimated costs, quality-adjusted life years (QALYs), life-years, and incremental cost-effectiveness ratios (ICERs) for workplace-based management compared with routine care in both the study period and over a lifetime. Analyses are conducted from the societal perspective. Over the 10-year follow-up, patients in the management group experienced an average gain of 0.06 QALYs with associated incremental costs of $633.17 (4366.85 RMB). Projecting over a lifetime, the management group was estimated to increase by 0.88 QALYs or 0.92 life-years compared with the control group, with an incremental cost of $1638.64 (11 301.37 RMB). This results in an incremental cost-effectiveness ratio of $1855.47 per QALY gained and $1780.27 per life-year gained, respectively, when comparing workplace-based management with routine care. In probabilistic sensitivity analyses, with a threshold willingness-to-pay of $30 765 per QALY (3 times 2019 gross domestic product per capita), the management group showed a 100% likelihood of being cost-effective in 10 000 samples. CONCLUSIONS: Workplace-based management, compared with routine care for Chinese men with hypertension, could be cost-effective both during the study period and over a lifetime, and might be considered in working populations in China and elsewhere.

Nonlinear relationship between high-density lipoprotein cholesterol and cardiovascular disease: an observational and Mendelian randomization analysis.

BACKGROUND: Clinical trials and Mendelian randomization (MR) studies reported null effects of high-density lipoprotein cholesterol (HDL-C) on risk of cardiovascular disease (CVD), which might have overlooked a nonlinear causal association. We aimed to investigate the dose-response relationship between circulating HDL-C concentrations and CVD in observational and MR frameworks. METHODS: We included 348,636 participants (52,919 CVD cases and 295,717 non-cases) of European ancestry with genetic data from the UK Biobank (UKB) and acquired genome-wide association summary data for HDL-C of Europeans from the Global Lipids Genetics Consortium (GLGC). Observational analyses were conducted in the UKB. Stratified MR analyses were conducted combing genetic data for CVD from UKB and lipids from GLGC. RESULTS: Observational analyses showed L-shaped associations of HDL-C with CVD, with no further risk reduction when HDL-C levels exceeded 70 mg/dL. Multivariable MR analyses across entire distribution of HDL-C found no association of HDL-C with CVD, after control of the pleiotropic effect on other lipids and unmeasured pleiotropism. However, in stratified MR analyses, significant inverse associations of HDL-C with CVD were observed in the stratum of participants with HDL-C ≤ 50 mg/dL (odds ratio per unit increase, 0.86; 95 % confidence interval, 0.79-0.94), while null associations were observed in any stratum above 50 mg/dL. CONCLUSIONS: Our data suggest a potentially causal inverse association of HDL-C at low levels with CVD risks. These findings advance our knowledge about the role of HDL as a potential target in CVD prevention and therapy.

Nuclear Magnetic Resonance-Based Metabolomics and Risk of CKD.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) leads to lipid and metabolic abnormalities, but a comprehensive investigation of lipids, lipoprotein particles, and circulating metabolites associated with the risk of CKD has been lacking. We examined the associations of nuclear magnetic resonance (NMR)-based metabolomics data with CKD risk in the UK Biobank study. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A total of 91,532 participants in the UK Biobank Study without CKD and not receiving lipid-lowering therapy. EXPOSURE: Levels of metabolites including lipid concentration and composition within 14 lipoprotein subclasses, as well as other metabolic biomarkers were quantified via NMR spectroscopy. OUTCOME: Incident CKD identified using ICD codes in any primary care data, hospital admission records, or death register records. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: We identified 2,269 CKD cases over a median follow-up period of 13.1 years via linkage with the electronic health records. After adjusting for covariates and correcting for multiple testing, 90 of 142 biomarkers were significantly associated with incident CKD. In general, higher concentrations of very-low-density lipoprotein (VLDL) particles were associated with a higher risk of CKD whereas higher concentrations of high-density lipoprotein (HDL) particles were associated with a lower risk of CKD. Higher concentrations of cholesterol, phospholipids, and total lipids within VLDL were associated with a higher risk of CKD, whereas within HDL they were associated with a lower risk of CKD. Further, higher triglyceride levels within all lipoprotein subclasses, including all HDL particles, were associated with greater risk of CKD. We also identified that several amino acids, fatty acids, and inflammatory biomarkers were associated with risk of CKD. LIMITATIONS: Potential underreporting of CKD cases because of case identification via electronic health records. CONCLUSIONS: Our findings highlight multiple known and novel pathways linking circulating metabolites to the risk of CKD. PLAIN-LANGUAGE SUMMARY: The relationship between individual lipoprotein particle subclasses and lipid-related traits and risk of chronic kidney disease (CKD) in general population is unclear. Using data from 91,532 participants in the UK Biobank, we evaluated the associations of metabolites measured using nuclear magnetic resonance testing with the risk of CKD. We identified that 90 out of 142 lipid biomarkers were significantly associated with incident CKD. We found that very-low-density lipoproteins, high-density lipoproteins, the lipid concentration and composition within these lipoproteins, triglycerides within all the lipoprotein subclasses, fatty acids, amino acids, and inflammation biomarkers were associated with CKD risk. These findings advance our knowledge about mechanistic pathways that may contribute to the development of CKD.

A correlation study between prostate necrosis rate calculated by 3D Slicer software and clinical efficacy of prostatic artery embolization, along with an analysis of predictors of clinical success after prostatic artery embolization.

PURPOSE: To analyze the correlation between the prostate necrosis rate at 1-month after prostatic artery embolization (PAE) and the clinical efficacy at 1-year after PAE, and to explore potential predictors of clinical success after PAE for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). METHODS: The prostate magnetic resonance imaging data at 1-month after PAE were imported into 3D Slicer software for calculating the prostate necrosis rate and thus analyzing the relationship between the prostate necrosis rate at 1-month after PAE and the efficacy score ratio at 1-year after PAE. The 151 patients with PAE technical success were divided into a clinical success group (n = 126) and a clinical failure group (n = 25). Independent predictors of clinical success after PAE were analyzed by multifactorial logistic regression, and the predictive performance of each factor was evaluated by applying the receiver operating characteristic curve and the area under the curve (AUC). RESULTS: There was a linear negative correlation between the prostate necrosis rate at 1-month after PAE and the efficacy score ratio at 1-year after surgery (P < 0.001). In the clinical success group, both the initial prostate volume (PV) and the prostate necrosis rate at 1-month after PAE were significantly higher than in the clinical failure group (P < 0.001), and acute urinary retention (AUR) and adenomatous-dominant BPH were also associated with clinical success (P < 0.05). Multifactorial logistic regression analysis revealed that larger initial PV, a higher prostate necrosis rate at 1-month after surgery, and AUR were independent predictors of clinical success after PAE. The AUC values for these three indicators and their combination were 0.720, 0.928, 0.599, and 0.951, respectively, in which the prostate necrosis rate at 1-month after PAE demonstrating a high predictive value. CONCLUSION: The higher the prostate necrosis rate at 1-month after PAE, the better the clinical efficacy at 1-year after PAE is likely to be, and the prostate necrosis rate at 1-month after PAE is expected to become a predictor of clinical success after PAE.

Global Burden of Ischemic Heart Disease in Adolescents and Young Adults, 1990-2019.

INTRODUCTION: Few studies have evaluated the global burden of ischemic heart disease (IHD) in adolescents and young adults (AYAs). METHODS: Age-standardized rates (ASRs) of incidence (ASIR), mortality (ASMR) and Disability-Adjusted Life Years (DALYs) (ASDR) were used to describe the burden of IHD in AYAs. Estimated Annual Percentage Changes (EAPCs) of ASRs were used to describe the trend from 1990 to 2019. Risk factors were calculated by population attributable fractions (PAFs). Analyses were conducted in 2023. RESULTS: In 2019, the ASIR, ASMR, and ASDR of IHD in AYAs were 26.81 (95% uncertainty interval [UI]: 20.36-34.54) per 100,000, 7.15 (95% UI: 6.56-7.87) per 100,000 and 409.51 (95% UI: 376.57-449.59) per 100,000. The ASIR and ASMR were higher among men than among women. From 1990 to 2019, the ASIR increased (EAPC=0.18%, 95% CI 0.14%-0.22%), while the ASMR (EAPC=-0.39%, -0.50% to -0.27%) and ASDR (EAPC=-0.40%, -0.52% to -0.29%) decreased. The largest increase in ASIR was observed in countries with a middle sociodemographic index (SDI) (EAPC=0.56%, 0.51%-0.60%). Globally, the proportional contribution of risk factors for DALY varied across regions, with the highest proportions of high low-density lipoprotein cholesterol in high SDI regions (PAF=74.26%) and high-middle (PAF=71.30%) and the highest proportions of air pollution in low (PAF=41.79%) and low-middle SDI regions (PAF=40.90%). CONCLUSIONS: The burden of IHD in AYAs remains high globally, and varies by age, sex, (male/female), region, and country. Targeted measures are needed to address the rising burden of IHD in AYAs, focusing on prevention, early diagnosis, and reduction in disparities.

Case Report: Imaging features of a new type double inferior vena cava malformation and review.

Background: Double inferior vena cava (DIVC) is a rare vascular malformation. With advances in radiological techniques and diagnosis, more and more types of DIVC were identified and diagnosed. Recognition of the variety of DIVC seen on imaging is essential for subsequent venous interventions. Case presentation: A 77-year-old man presented with low back pain with left lower limb pain for 1 month. Scattered petechiae above the skin surface on the left lower leg, especially on the extensor surface, with flaking and mild tingling of the skin, were noted 3 weeks ago. Ultrasound revealed deep vein thrombosis (DVT) in the left lower limb. Computed tomography pulmonary angiography (CTPA) suggested no significant thrombus in the pulmonary artery. Computed tomography venography (CTV) of bilateral lower limbs showed that iliac vein compression syndrome with formation of deep and superficial venous traffic branches in bilateral lower limbs, predominantly on the left side. CTV of the inferior vena cava (IVC) suggested that the left common iliac vein crossed the common iliac artery bifurcation from dorsal to ventral and continued to travel cranially as a ventral vessel, and connected with the ventral IVC anterior to the right common iliac artery. The right common iliac vein extended cephalad as a dorsal vessel, which was narrowed at the level of 4th lumbar vertebra by compression of the hyperplastic bone and the osteophyte. The patient was discharged after right and left common iliac vein angiography and balloon dilation of bilateral common iliac vein. Conclusion: The formation of both ventrally and dorsally aligned DIVC is rarer. It should be clarified the effects of DIVC on DVT formation, and the importance of imaging for preoperative planning.

Cost-effectiveness of drug treatment for young and middle-aged stage 1 hypertensive patients with high risk.

Background: Drug treatment was recommended for stage 1 hypertensive patients (blood pressure of 130-139 / 80-89 millimetres of mercury (mmHg)) with high cardiovascular disease (CVD) risk in the 2017 Hypertension Clinical Practice Guidelines, 2018 Chinese guidelines and 2021 World Health Organization guidelines, but not in other guidelines. However, evidence on the cost-effectiveness of drug treatment among young and middle-aged patients remains scarce. This study aimed to compare the cost-effectiveness of drug treatment vs. non-drug treatment for stage 1 hypertensive patients aged <60 years with high CVD risk. Methods: A microsimulation model projected quality-adjusted life years (QALYs), health care costs, and incremental cost-effectiveness ratios for drug treatment from a societal perspective. Transition probabilities were estimated from the Kailuan study with a sample size of 34 093 patients aged <60 years with high CVD risk. Costs and health utilities were obtained from the Kailuan study, national statistics reports and published literature. Results: Over a 15-year time horizon, the model predicted that drug treatment generated QALY of 9.36 and was associated with expected costs of 3735 US dollars ($) compared with 9.07 and $3923 produced by non-drug treatment among stage 1 hypertensive patients, resulting in a cost-saving for drug treatment. At a willingness-to-pay threshold of $10439/QALY (one gross domestic product (GDP) per capita in 2020), drug treatment had a 99.99% probability of being cost-effective for 10 000 samples of probabilistic sensitivity analysis. Sensitivity analyses by different values of transition probability, cost, utility and discount rate did not appreciably change the results. Shortening the time horizon to the average follow-up period of eight years resulted in ICER of $189/QALY for drug treatment (<1 × GDP/QALY). Conclusions: Our results suggested that drug treatment was a dominant strategy for stage 1 hypertensive patients aged <60 years with high CVD risk in China, which may provide evidence for policymakers and clinicians when weighing the pros and cons of drug treatment for young and middle-aged stage 1 hypertensive patients.

The impact of multiple metals exposure on the risk of developing proliferative diabetic retinopathy in Anhui, China: a case-control study.

Through multiple different pathways, the environmental multiple metals make their ways to the human bodies, where they induce different levels of the oxidative stress response. This study further investigated the impact of multiple-metal exposure on the risk of developing proliferative diabetic retinopathy (PDR). We designed a case-control study with type 2 diabetic patients (T2D), in which the case group was the proliferative diabetic retinopathy group (PDR group), while the control group was the non-diabetic retinopathy group (NDR group). Graphite furnace atomic absorption spectrometry (GFAAS) and inductively coupled plasma optical emission spectrometry (ICP-OES) were used to detect the metal levels in our participants' urine samples. The least absolute shrinkage and selection operator (LASSO) regression approach was used to include these representative trace elements in a multiple exposure model. Following that, logistic regression models and Bayesian kernel machine regression (BKMR) models were used to describe the effect of different elements and also analyze their combined effect. In the single-element model, we discovered that lithium (Li), cadmium (Cd), and strontium (Sr) were all positively related to PDR. The multiple-exposure model revealed a positive relationship between Li and PDR risk, with a maximum quartile OR of 2.80 (95% CI: 1.10-7.16). The BKMR model also revealed that selenium (Se) might act as a protective agent, whereas magnesium (Mg), Li, and Cd may raise the risk of PDR. In conclusion, our study not only revealed an association between exposure to multiple metals and PDR risk but it also implied that urine samples might be a useful tool to assess PDR risk.

Adherence to a Planetary Health Diet, Environmental Impacts, and Mortality in Chinese Adults.

Importance: Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. Objective: To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. Design, Setting, and Participants: This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. Exposures: PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Main Outcomes and Measures: Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. Results: A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (ß = -0.13 kg CO2 equivalent; 95% CI, -0.14 to -0.12 kg CO2 equivalent), but with higher total water footprint (ß = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (ß = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). Conclusions and Relevance: In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use.

Associations of Clinical Risk Factors and Novel Biomarkers With Age at Onset of Type 2 Diabetes.

CONTEXT: Younger onset of type 2 diabetes (T2D) was associated with higher risks of vascular complications and mortality. OBJECTIVE: To prospectively assess risk profiles for incident T2D stratified by age at onset. METHODS: A total of 471 269 participants free of T2D at baseline were included from the UK Biobank. Approximately 70 clinical, lipid, lipoprotein, inflammatory, and metabolic markers, and genetic risk scores (GRSs) were analyzed. Stratified Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) for T2D with age of diagnosis divided into 4 groups (≤50.0, 50.1-60.0, 60.1-70.0, and >70.0 years). RESULTS: During 11 years of follow-up, 15 805 incident T2D were identified. Among clinical risk factors, obesity had the highest HR at any age, ranging from 13.16 (95% CI, 9.67-17.91) for 50.0 years and younger to 4.13 (3.78-4.51) for older than 70.0 years. Other risks associated with T2D onset at age 50.0 years and younger included dyslipidemia (3.50, 2.91-4.20), hypertension (3.21, 2.71-3.80), cardiovascular disease (2.87, 2.13-3.87), parental history of diabetes (2.42, 2.04-2.86), education lower than college (1.89, 1.57-2.27), physical inactivity (1.73, 1.43-2.10), smoking (1.38, 1.13-1.68), several lipoprotein particles, inflammatory markers, liver enzymes, fatty acids, amino acids, as well as GRS. Associations of most risk factors and biomarkers were markedly attenuated with increasing age at onset (P interaction <.05), and some were not significant for onset at age older than 70.0 years, such as smoking, systolic blood pressure, and apolipoprotein B. CONCLUSION: Most risk factors or biomarkers had stronger relative risks for T2D at younger ages, which emphasizes the necessity of promoting primary prevention among younger individuals. Moreover, obesity should be prioritized.

Nutrition and Healthy Ageing in Asia: A Systematic Review.

BACKGROUND: Nutrition plays a key role in modulating the likelihood of healthy ageing. In the present study, we aimed to conduct a systematic review to assess the impact of nutrition on healthy ageing in Asia. METHODS: The systematic review was registered in the International Prospective Register of Systematic Reviews database (CRD42023408936) and conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed, Web of Science, and Embase databases were searched up to February 2023 without language restrictions. We included prospective cohort studies that evaluated the associations of intake of a single food or consumption of a single nutrient at midlife; adherence to various dietary patterns at midlife; and improved adherence to dietary patterns from mid- to late life with the likelihood of healthy ageing and its components. RESULTS: Out of 16,373 records, we included 71 papers comprising 24 cohorts from Singapore, China, Japan, and Thailand. The healthy ageing components included cognitive function, physical function, and depression. The majority of studies supported the observation that the likelihood of healthy ageing and its components in late life was positively increased by a higher consumption of healthy foods, such as vegetables, fruits, fish, nuts, legumes, tea, milk, and dairy, at midlife, and also by greater adherence to dietary patterns with high diversity scores or high total antioxidant capacities. Furthermore, improved adherence to healthy dietary patterns from mid- to late life also increased the likelihood of healthy ageing in late life. CONCLUSION: Consuming healthy foods and adhering to healthy dietary patterns at midlife can promote the likelihood of healthy ageing. Moreover, improving diet quality from mid- to late life can still be beneficial.

Safety and Efficacy of Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma: A Single Center Experience.

Purpose: In China, many patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. Several studies have shown that triple therapy [transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] is beneficial for patient survival. In this study, we aimed to evaluate the efficacy of triple therapy (TACE + TKIs + ICIs) for unresectable HCC (uHCC) and the conversion rate of surgical resection (SR). The primary endpoints were objective response rate (ORR) and disease control rate (DCR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 and adverse events (AEs), while the secondary endpoint was the conversion rate of patients with uHCC treated with triple therapy followed by SR. Patients and Methods: Forty-nine patients with uHCC who received triple therapy at Fujian Provincial Hospital between January 2020 and June 2022 were retrospectively included. The treatment efficacy, SR conversion rate, and associated AEs were recorded. Results: Among the 49 patients enrolled, the ORRs assessed by mRECIST and RECIST v1.1 were 57.1% (24/42) and 14.3% (6/42), respectively, and the DCRs were 92.9% (39/42) and 88.1% (37/42), respectively. Seventeen (34.7%) patients met the criteria for resectable HCC and underwent resection. The median interval between the start of triple therapy and resection was 113.5 days (range 94.75 to 182 d), and the median number of TACE was 2 (range 1 to 2.5). The patients did not achieve median overall survival or median progression-free survival. Treatment-related AEs occurred in 48 (98%) patients, and 18 (36.7%) patients had grade ≥3 AEs. Conclusion: Triple combination therapy resulted in a relatively high ORR and conversion resection rate following uHCC treatment.

Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Lenvatinib and Anti-PD-1 Antibodies for Unresectable Hepatocellular Carcinoma: A Retrospective Analysis.

Background: Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC. Methods: Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred. Conclusion: DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.

KLF9 inhibits the proliferation, invasion, and migration of renal cell carcinoma through the SDF-1/CXCR4 axis.

Altered Krüppel-like factor 9 (KLF9) expression can regulate the progression of several cancers, including renal cell carcinoma (RCC). This study was conducted to investigate the role of KLF9 in the proliferation, invasion, and migration of RCC cells via regulation of stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). The expression patterns of KLF9, SDF-1, and CXCR4 in the experimental cell lines were determined by real-time quantitative polymerase chain reaction and Western blotting. After transfection of the KLF9 siRNA and KLF9 pcDNA, cell proliferation, invasion, and migration were evaluated by experiments including cell counting kit-8, colony formation, and Transwell assays. The binding of KLF9 to the SDF-1 promoter was analyzed by chromatin immunoprecipitation and dual-luciferase assay. The rescue experiment was performed using the recombinant SDF-1 protein and KLF9 pcDNA. KLF9 was downregulated in the RCC cells. KLF9 knockdown induced the proliferation, invasion, and migration of RCC cells, whereas KLF9 overexpression elicited the opposite roles. Mechanically, KLF9 bound to the SDF-1 promoter, repressed SDF-1 transcription, and reduced the SDF-1/CXCR4 expression levels. Activation of the SDF-1/CXCR4 axis attenuated the inhibitory role of KLF9 overexpression in RCC cell growth. Ordinarily, KLF9 suppressed the proliferation, invasion, and migration of RCC cells by repressing the SDF-1/CXCR4 signaling.

Differences in HDL-related mortality risk between individuals with and without hypertension: a prospective cohort study in UK Biobank.

BACKGROUND AND AIMS: Very high levels of high-density lipoprotein cholesterol (HDL-C) have been paradoxically linked to increased mortality risk. The present study aimed to examine associations of HDL-C and varied sizes of the HDL particle (HDL-P) with mortality risk stratified by hypertension. METHODS AND RESULTS: This prospective cohort study included 429 792 participants (244 866 with hypertension and 184 926 without hypertension) from the UK Biobank. During a median follow-up of 12.7 years, 23 993 (9.8%) and 8142 (4.4%) deaths occurred among individuals with and without hypertension, respectively. A U-shaped association of HDL-C with all-cause mortality was observed in individuals with hypertension after multivariable adjustment, whereas an L-shape was observed in individuals without hypertension. Compared with individuals with normal HDL-C of 50-70 mg/dL, those with very high HDL-C levels (>90 mg/dL) had a significantly higher risk of all-cause mortality among individuals with hypertension (hazard ratio, 1.47; 95% confidence interval, 1.35-1.61), but not among those without hypertension (1.05, 0.91-1.22). As for HDL-P, among individuals with hypertension, a larger size of HDL-P was positively whereas smaller HDL-P was negatively associated with all-cause mortality. After additional adjustment for larger HDL-P in the model, the U-shaped association between HDL-C and mortality risk was altered to an L-shape among individuals with hypertension. CONCLUSIONS: The increased risk of mortality associated with very high HDL-C existed only in individuals with hypertension, but not in those without hypertension. Moreover, the increased risk at high HDL-C levels in hypertension was likely driven by larger HDL-P.

This study examined the potential modification of hypertension on associations of high-density lipoprotein cholesterol (HDL-C), especially at a very high level, and varied sizes of HDL particle (HDL-P) with the risk of mortality.Very high HDL-C levels were associated with increased risk of mortality in individuals with hypertension, but not in those without hypertension.In individuals with hypertension, the increased risk at a high HDL-C level was attributed to a larger size of HDL-P, which was directly associated with mortality risk. An inverse association with mortality was observed for a smaller size of HDL-P.

Association of Combined Healthy Lifestyles With Cardiovascular Disease and Mortality of Patients With Diabetes: An International Multicohort Study.

OBJECTIVE: To prospectively examine the associations of combined lifestyle factors with incident cardiovascular disease (CVD) and mortality in patients with diabetes. PATIENTS AND METHODS: Patients with prevalent diabetes were included from 5 prospective, population-based cohorts in China (Dongfeng-Tongji cohort and Kailuan study), the United Kingdom (UK Biobank study), and the United States (National Health and Nutrition Examination Survey and National Institutes of Health-AARP Diet and Health Study). Healthy lifestyle scores were constructed according to non-current smoking, low to moderate alcohol drinking, regular physical activity, healthy diet, and optimal body weight; the healthy level of each lifestyle factor was assigned 1 point, or 0 for otherwise, and the range of the score was 0 to 5. Cox proportional hazards models were used to estimate hazard ratios for incident CVD, CVD mortality, and all-cause mortality adjusting for sociodemographic, medical, and diabetes-related factors, and outcomes were obtained by linkage to medical records and death registries. Data were collected from October 18, 1988, to September 30, 2020. RESULTS: A total of 6945 incident CVD cases were documented in 41,350 participants without CVD at baseline from the 2 Chinese cohorts and the UK Biobank during 389,330 person-years of follow-up, and 40,353 deaths were documented in 101,219 participants from all 5 cohorts during 1,238,391 person-years of follow-up. Adjusted hazard ratios (95% CIs) comparing patients with 4 or 5 vs 0 or 1 healthy lifestyle factors were 0.67 (0.60 to 0.74) for incident CVD, 0.58 (0.50 to 0.68) for CVD mortality, and 0.60 (0.53 to 0.68) for all-cause mortality. Findings remained consistent across different cohorts, subgroups, and sensitivity analyses. CONCLUSION: The international analyses document that adherence to multicomponent healthy lifestyles is associated with lower risk of CVD and premature death of patients with diabetes.